Cancer-cell stiffening via cholesterol depletion enhances adoptive T-cell immunotherapy
Name
EMS137630.pdf
Description
Accepted version
Size
2.87 MB
Format
Adobe PDF
Checksum (MD5)
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Author(s)
Lei, Kewen
Kurum, Armand
Kaynak, Murat
Bonati, Lucia
Han, Yulong
Cencen, Veronika
Gao, Min
Xie, Yu-Qing
Guo, Yugang
Hannebelle, Mélanie TM
Date Issued
2021
Journal
Nature Biomedical Engineering
Publisher
Springer Science and Business Media LLC
Citation
Lei, Kewen, Kurum, Armand, Kaynak, Murat, Bonati, Lucia, Han, Yulong et al. 2021. "Cancer-cell stiffening via cholesterol depletion enhances adoptive T-cell immunotherapy." Nature Biomedical Engineering, 5 (12).
Version
Author's final manuscript
Abstract
Malignant transformation and tumour progression are associated with cancer-cell softening. Yet how the biomechanics of cancer cells affects T-cell-mediated cytotoxicity and thus the outcomes of adoptive T-cell immunotherapies is unknown. Here we show that T-cell-mediated cancer-cell killing is hampered for cortically soft cancer cells, which have plasma membranes enriched in cholesterol, and that cancer-cell stiffening via cholesterol depletion augments T-cell cytotoxicity and enhances the efficacy of adoptive T-cell therapy against solid tumours in mice. We also show that the enhanced cytotoxicity against stiffened cancer cells is mediated by augmented T-cell forces arising from an increased accumulation of filamentous actin at the immunological synapse, and that cancer-cell stiffening has negligible influence on: T-cell-receptor signalling, production of cytolytic proteins such as granzyme B, secretion of interferon gamma and tumour necrosis factor alpha, and Fas-receptor-Fas-ligand interactions. Our findings reveal a mechanical immune checkpoint that could be targeted therapeutically to improve the effectiveness of cancer immunotherapies.
MIT Department
Massachusetts Institute of Technology. Department of Mechanical Engineering
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Creative Commons Attribution-Noncommercial-Share Alike
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DOI of Published Version
https://doi.org/10.1038/S41551-021-00826-6
